Cells have a checkpoint mechanism by which the cell cycle is temporarily arrested in response to DNA damage to allow for DNA repair [Cell Proliferation, Vol. 33, pp. 261-274]. In about half of human cancers, the G1 checkpoint function is lost by the mutation or defect of the cancer suppressior gene p53. However, such cancer cells still have the G2 checkpoint function, and this is believed to be a factor causing a reduction in sensitivity to DNA-acting anticancer agents and radiations.
Wee1 kinase is a tyrosine kinase involved in the G2 checkpoint of the cell cycle. Wee1 temporarily arrests the cell cycle at the G2 phase by inactivating Cdc2 through the tyrosine 15 phosphorylation of Cdc2 (Cdk1) involved in the G2 to M phase transition of the cell cycle [The EMBO Journal, Vol. 12, pp. 75-85]. Therefore, in p53 defect cancer cells, the role of Wee1 in the G2 checkpoint function is considered to be important for the repair of DNA at the time of DNA damage to avoid cell death. There have been reports that the attenuation of Wee1 expression by RNA interference, or inhibition of Wee1 using compounds enhances sensitivity of cancer cells to adriamycin, X-rays, and γ-rays [Cancer Biology & Therapy, Vol. 3, pp. 305-313, and Cancer Research, Vol. 61, pp. 8211-8217]. It is therefore believed that Wee1 inhibitor, through inhibition of the G2 checkpoint function in p53 defect cancer cells, can improve sensitivity to DNA-acting anticancer agents or radiations.
Low molecular Wee1 kinase inhibitor compounds are known, as described in, for example, US Patent Application Publication US2005/0250836 (Patent Document 1), Pamphlet of International Publication 2003/091255 (Patent Document 2), Cancer Research, Vol. 61, pp. 8211-8217 (Non-Patent Document 1), and Bioorg & Med. Chem. Lett., Vol. 15, pp. 1931-1935 (Non-Patent Document 2). However, the compounds described in these publications are completely different in structure from a compound of the present invention.
Pamphlet of International Publication 99/61444 (Patent Document 3) and Pamphlet of International Publication 2004/041823 (Patent Document 4) disclose compounds relatively similar to a compound of the present invention in part of the structure. However, these publications do not disclose or even suggest the compound as described in the present invention.